Li Q, Zhang J, Loro J F, Pfaffendorf M, van Zwieten P A
Department of Pharmacotherapy, University of Amsterdam, The Netherlands.
J Cardiovasc Pharmacol. 1998 Sep;32(3):452-6. doi: 10.1097/00005344-199809000-00016.
The positive chronotropic effect of bradykinin was investigated in isolated spontaneously beating atria of the rat. Cumulative additions of bradykinin (0.3-100 nM) caused a concentration-dependent increase in the beating rate of the atria by maximally 35+/-4 beats/min, approximately 25% of the 1 microM isoprenaline-induced maximal responses. In contrast, the active metabolite of bradykinin and selective bradykinin B1-receptor agonist, Des-Arg9-bradykinin, did not influence the spontaneous frequency of beating. Propranolol (1 microM) combined with prazosin (1 microM) did not affect the positive chronotropic effect of bradykinin. A selective bradykinin B2-receptor antagonist, Hoe 140, concentration-dependently shifted the response curves for bradykinin to the right, whereas the bradykinin B1-receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin had no effect. The tachycardic responses to bradykinin were potentiated by ramipril, an angiotensin-converting enzyme/kininase II inhibitor, but not affected by Nomega-nitro-L-arginine methyl ester hydrochloride, a nitric oxide synthesis inhibitor. Indomethacin and meclofenamate, two cyclooxygenase inhibitors, abolished the bradykinin-induced chronotropic effect. These results indicate that exogenous bradykinin induces a positive chronotropic effect that occurs independent of adrenoceptors. The bradykinin-induced chronotropic effect is mediated by bradykinin B2 receptors, whereas B1 receptors do not play a role in mediating this effect. Prostaglandins but not nitric oxide appear to be involved in bradykinin-induced positive chronotropic effect.
在大鼠离体自搏性心房中研究了缓激肽的正性变时作用。累积添加缓激肽（0.3 - 100 nM）可使心房搏动频率呈浓度依赖性增加，最大增加35±4次/分钟，约为1μM异丙肾上腺素诱导的最大反应的25%。相比之下，缓激肽的活性代谢产物及选择性缓激肽B1受体激动剂去精氨酸9 - 缓激肽并不影响自发搏动频率。普萘洛尔（1μM）与哌唑嗪（1μM）联合应用不影响缓激肽的正性变时作用。选择性缓激肽B2受体拮抗剂Hoe 140可使缓激肽的反应曲线浓度依赖性右移，而缓激肽B1受体拮抗剂Lys - [Leu8]去精氨酸9 - 缓激肽则无此作用。血管紧张素转换酶/激肽酶II抑制剂雷米普利可增强缓激肽引起的心动过速反应，但一氧化氮合成抑制剂盐酸Nω-硝基-L-精氨酸甲酯对此无影响。两种环氧化酶抑制剂吲哚美辛和甲氯芬那酸可消除缓激肽诱导的变时作用。这些结果表明，外源性缓激肽可诱导不依赖于肾上腺素能受体的正性变时作用。缓激肽诱导的变时作用由缓激肽B2受体介导，而B1受体在介导此作用中不起作用。前列腺素而非一氧化氮似乎参与了缓激肽诱导的正性变时作用。
